tbuckley/cabot-search huggingface dataset:
ANTICIPATE phase I: Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).
Authors: Matt D. Galsky, John P. Sfakianos, Ding-Wei Ye, Xiaodong Song, Hailong Hu, Neal D. Shore, Xiaoping Zhang, Mingming Zhang
Journal: Journal of Clinical Oncology (2023)

e16607 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: ANTICIPATE Phase I was a dose escalation study to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of APL-1202. Eligible patients had newly diagnosed MIBC, were cisplatin-ineligible or refused cisplatin-based neoadjuvant chemotherapy, and were planned for radical cystectomy (RC). A standard 3+3 dose-escalation design was employed. On day 1 of each cycle, a single dose of 200 mg tislelizumab was administered intravenously. APL-1202 was administered orally 3 times daily and with the dose escalated in 3 successive cohorts (375 mg, 750 mg, and 1,125 mg). Intra-patient dose escalation was not allowed. Blood samples were collected for pharmacokinetics and other translational studies. Results: Nine patients have been enrolled in phase I: 3 patients each at 375 mg, 750 mg, and 1125 mg of APL-1202. All patients had predominant urothelial cancer with cT2 (6/9) and cT3 (3/9); PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay and 1/9 (11.1%) patients was positive. No dose-limiting toxicities were observed at either 375 mg, 750 mg, or 1125 mg daily dose of APL-1202. Treatment-related adverse events (TRAE) were observed in 6 patients. All AEs were grade 1, except 1 grade 2 T wave abnormality on ECG and 1 grade 3 liver dysfunction. No grade 4 or 5 related AEs were observed. The patient with grade 3 liver dysfunction recovered to baseline within 2 weeks and underwent RC. Pathologic downstaging to &lt; pT2 was observed in 5/8 (62.5%) and 1/8 (12.5%) with pT0 in 8 evaluable patients; 1 patient refused RC. Conclusions: APL-1202 plus tislelizumab was well tolerated. The RP2D of APL-1202 was identified as 1125 mg daily dose. Early efficacy signals were observed including pathologic downstaging to &lt; pT2 (5/8, 62.5%) and pT0 (1/8, 12.5%). Phase 2 trial was ongoing. (NCT04813107). Clinical trial information: NCT04813107 .
Alliance A022102: Randomized phase III trial of mFOLFIRINOX +/- nivolumab vs. FOLFOX +/- nivolumab for first-line treatment of metastatic HER2-negative gastroesophageal adenocarcinoma (GEA).
Authors: Haeseong Park, Susan Michelle Geyer, Kelsey Klute, Jonathan Bleeker, Daniel King, Matthew Strickland, Austin Goodrich, Destin Carlisle, Ardaman Shergill, Eileen Mary O'Reilly, Jeffrey A. Meyerhardt, Manish A. Shah
Journal: Journal of Clinical Oncology (2023)

TPS4175 Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m 2 , leucovorin 400 mg/m 2 , oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score &gt; 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .
Unique molecular underpinnings by genetic ancestry in localized clear cell renal cell carcinoma.
Authors: Roy Elias, Thomas Nirschl, Michael Rezaee, Anirudh Yerrapragada, Shirley Wang, Joseph G. Cheaib, Ridwan Alam, Sunil H. Patel, Yuezhou Jing, Mohamad E. Allaf, Srinivasan Yegnasubramanian, Yasser Ged, Nirmish Singla
Journal: Journal of Clinical Oncology (2023)

4536 Background: Clinical studies evaluating the impact of race on outcomes in renal cell carcinoma (RCC) are inconsistent and conceivably influenced by both biological and socioeconomic factors. Self-reported African Americans (AA) are also largely underrepresented in clinical trials and molecular studies of clear cell (cc) RCC compared to their White (W) counterparts. Herein, we sought to comprehensively characterize molecular differences by genetic ancestry in localized ccRCC. Methods: We performed whole exome (WES) and transcriptome (RNAseq) sequencing on a case-matched cohort of AA and W patients (pts) who underwent nephrectomy for localized ccRCC at our institution. Germline single nucleotide polymorphisms were combined with reference panels from the 1000 Genomes Project, and ancestry was estimated using ADMIXTURE. Molecular subtypes were defined according to the IMmotion151 (IMm151) subtypes, and a random forest model was trained to predict subgroups. Results: From an initial selected cohort of 84 pts, WES and RNAseq data of adequate quality were available for 61 pts including 28 of African (AFR) and 33 of European (EUR) descent. We augmented our institutional cohort with a 3:1 EUR:AFR matched subset of the TCGA KIRC by stage, nuclear grade (NG), and gender. The final analytic cohort contained 75 pts of AFR and 177 pts of EUR descent. There were no significant differences in stage, NG, or gender between AFR and EUR groups. We observed that VHL [OR 0.22, CI [0.11-0.43], p &lt;0.001) and PBRM1 (OR 0.4, CI [0.19-0.79], p = 0.005) mutations are enriched in pts with EUR ancestry and identified a unique association of KMT2C somatic mutations (OR 3.7, CI [1.1-13.5], p = 0.027) with AFR ancestry. Consistent with a lower frequency of VHL mutations, gene-set variation analysis revealed lower enrichment for angiogenesis (-0.23 vs 0.045; p &lt; 0.001) in AFR vs EUR ancestry, respectively. AFR ancestry was associated with an increased proportion of the “Proliferative” IMm151 subtype (14.9% [n = 11/74] vs 3.4% [n = 6/177], p = 0.002). There was no association between overall survival (OS) and ancestry; however, IMm151 subtypes stratified OS with longest survival in the “Angiogenic/Stromal” group (median OS NR) and shortest OS in the T-Effector/Proliferative subtype (5.5yrs CI [2.3 - NR], p = 0.01). Conclusions: Our findings indicate that genetic ancestry is associated with distinct molecular subtypes of ccRCC. Biological drivers of ccRCC pathogenesis and therapeutic response may vary by ancestry, underscoring the need for racially diverse representation in future studies.
Association of early completion of portable medical orders with inpatient costs at end-of-life for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
Authors: Marissa LoCastro, Andrea M. Baran, Jane Liesveld, Eric Huselton, Kah Poh Loh, Jason Mendler
Journal: Journal of Clinical Oncology (2023)

6645 Background: Patients with hematologic malignancies receive more aggressive care at end-of-life (EOL) compared to patients with solid tumors. Costs of care in patients with hematologic malignancies at EOL are high, particularly in the inpatient setting. We previously found that early completion of portable medical orders [termed medical orders for life sustaining treatment (MOLST) in New York state] is associated with less intense care at EOL for patients with AML and MDS. Thus, we hypothesized that early MOLST completion would also be associated with lower inpatient costs at EOL among patients with AML and MDS. Methods: We previously conducted a retrospective study of 358 adults patients with AML or MDS treated at Wilmot Cancer Institute and its affiliated sites who died between January 1, 2014, and December 31, 2019. Of these, 271 patients were eligible for cost analysis. Cost of inpatient care received at the University of Rochester Medical Center (URMC) within the last 30 days of life was obtained from our Finance Decision Support Department. Patients were excluded if inpatient costs at EOL were unavailable. Results: Mean age of patients was 69 years (N=271, range 20-95); 84% (n=227) of patients were hospitalized within 30 days of death. One-third (34%, n=93) of patients completed a MOLST early (&gt;30 days prior to death) whereas 66% (n=178) either did not complete a MOLST or completed a MOLST late (less than or equal to 30 days prior to death). Mean and median inpatient cost of care for all patients at EOL was $39,284 and $19,703, respectively. The rate of hospitalization was lower for patients who completed a MOLST early vs late/never (73.1% vs 90.5%, respectively; p=0.0003), although there was no difference in the number of inpatient visits between the two groups (median=1 visit in both groups; p=0.23). In addition, median cost of inpatient care was lower for patients who completed a MOLST early vs late/never ($10,673 vs $23,177, respectively; p&lt;0.0001). After adjusting for age, sex, and diagnosis, there was a trend toward lower EOL costs in patients completing a MOLST early (p=0.07). Conclusions: In patients with AML or MDS, early MOLST completion may be associated with lower inpatient costs at EOL. Viewing MOLST completion as a surrogate for a goals-of-care discussion, it follows that interventions aimed to increase the frequency of early goals-of-care discussions, advanced care planning, and MOLST completion are likely to improve quality of care and decrease costs at EOL in these patient populations.
Comparing the efficacy of abiraterone and enzalutamide in United States veterans with metastatic castration-sensitive prostate cancer (mCSPC) by estimating rates of tumor growth (<i>g</i>-rate).
Authors: Harshraj Leuva, Mengxi Zhou, Rumen Stamatov, Benjamin A. Teply, Ta-Chueh Melody Rosenberg, Carol A. Luhrs, Prabhjot Singh Mundi, Yeun-Hee Anna Park, Susan Elaine Bates, Izak Faiena, Antonio Tito Fojo
Journal: Journal of Clinical Oncology (2023)

5076 Background: The choice of 1 st line novel hormonal therapy in mCSPC is often based on comorbidities/physician preference due to the lack of data comparing abiraterone (Abi) and enzalutamide (Enza) in clinical trials and in real-world settings; especially in Black American (BA) patients. We have developed a novel method to estimate rates of tumor growth ( g-rate) and have shown that the g-rate is a robust biomarker of drug efficacy and overall survival in prostate cancer (Wilkerson, 2017; Leuva, 2019). We performed a 1:1 matched analysis to compare Abi and Enza outcomes in 1 st line mCSPC, using g-rate and median overall survival (mOS) estimates. Methods: All patients with mCSPC diagnosis in national VA Corporate Data Warehouse were eligible for comparison. The cohort date range was from 7/2017 to 6/2022. Drug efficacy was established by estimating g-rates using PSA values while on therapy via the TUMGr package for R. For the matched analyses, we created 1:1 comparison cohorts for Abi and Enza, matched on age (±10 years), race, total number of therapies received (1/≥2), drug start year (&lt;2020/≥2020), PSA at diagnosis (&lt;20/≥20), Gleason score (GS) (&lt;8/≥8), Charlson comorbidity index excluding cancer diagnosis (&lt;5/≥5) and therapy setting (urban/rural). Results: We identified a total of 1712 and 464 Veterans with mCSPC who received Abi and Enza as 1 st line, with median follow-ups of 19 and 12 mo, respectively. Fewer Veterans and shorter duration of follow up with Enza than Abi reflect Abi’s earlier approval in mCSPC. The Abi and Enza cohorts had similar median g-rates 0.000114/d and 0.000110/d, respectively (p=0.76). The mOS was 43 mo for Abi versus not reached (NR) for Enza (p=0.33). Our cohort had 425(25%) and 119(26%) BA veterans who received Abi and Enza, respectively. Compared to Caucasians, mOS was similar with Abi (42.7 vs 41.9 mo, HR-0.96, p=0.6) and Enza (NR, HR-0.85, p=0.4) for BA. In 1:1 matched analysis, the Abi and Enza arms had 391 patients and both had median follow-ups of 13 mo. We did not observe a statistically significant difference in median g-rate and mOS for either the whole matched cohort or BA subgroup when comparing Abi to Enza. The matched cohort had 203 (52%) with GS ≥8 and 228 (58%) Veterans with PSA ≥20 at diagnosis; there was no significant mOS difference in these subgroups. Conclusions: Real-world data from 2176 Veterans show comparable efficacy for Abi and Enza as 1 st line for mCSPC, with similar g-rates and mOS, even when matched on various factors, including comorbidities, and in aggressive/high volume matched cohorts. BA patients also had similar g-rates and mOS. [Table: see text]
Efficacy and safety of HepaSphere drug-eluting bead transarterial chemoembolization combined with hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma.
Authors: Baojiang Liu, Song Gao, Jianhai Guo, Fuxin Kou, Shaoxing Liu, Xin Zhang, Aiwei Feng, Xiaodong Wang, Guang Cao, Hui Chen, Peng Liu, Haifeng Xu, Qinzong Gao, Renjie Yang, Xu Zhu
Journal: Journal of Clinical Oncology (2023)

4122 Background: Transarterial chemoembolization (TACE) is widely applied and shows good efficacy in advanced hepatocellular carcinoma (HCC). Recently, hepatic arterial infusion chemotherapy (HAIC) has also gained popularity in the treatment of HCC. Several studies have described the comparison between HAIC and TACE or TACE combined with HAIC. However, the evaluation between TACE plus HAIC and HAIC is rarely reported. Here, we observed the performance of HepaSphere DEB-TACE combined with HAIC (Hepa-HAIC) comparing to HAIC in patients with advanced HCC. Methods: 167 patients diagnosed as advanced HCC and treated in Peking University Cancer Hospital from May 2018 to May 2022 were enrolled in this retrospective study, composed of 74 patients received HepaSphere DEB-TACE combined with HAIC-FOLFOX (Hepa-HAIC) and 93 patients received HAIC-FOLFOX. More than 60% patients experienced other treatments before the enrollment. To avoid the selection bias, propensity score matching (PSM) was conducted and applied for the efficacy and safety analysis between these two cohorts. The primary endpoints are progression-free survival (PFS) and overall survival (OS); the secondary endpoint includes objective response rate (ORR), disease control rate (DCR) and safety. Results: Propensity-matching yielded 48 pairs and the baselines were almost equal in Hepa-HAIC and HAIC cohorts after matching. Median PFS and median OS were both higher in matched Hepa-HAIC cohort (median PFS:8.9 vs. 5.8 months, P=0.035; median OS:22.4 vs. 9.5 months, P=0.027), which were consistent with pre-matching analysis. The ORR in Hepa-HAIC and HAIC cohorts was 75.0% and 37.5%, respectively; DCR was 93.8% after Hepa-HAIC and 81.3% after HAIC. There was no treatment-related death. Serious adverse events were similar in these two groups, except alanine aminotransferase (ALT) and vomiting. There was more frequency of Grade 3–4 ALT elevation in Hepa-HAIC (33.3% vs. 8.3%, P=0.003) while more incidence of vomiting in HAIC group (29.2% vs. 12.5%, P=0.044). Conclusions: All of the observed PFS, OS, ORR and DCR in Hepa-HAIC group are superior to HAIC group, which indicates the combination of HepaSphere DEB-TACE and HAIC may lead to improved outcomes with comparable safety profile in advanced HCC. [Table: see text]
Incidence and risk of peripheral sensory neuropathy with enfortumab vedotin in patients with advanced urothelial cancer: A systematic review and meta-analysis.
Authors: Yousuf Shah, Amna Falak Sher, Shenhong Wu
Journal: Journal of Clinical Oncology (2023)

e16556 Background: Enfortumab Vedotin (EV), a first-in-class antibody-drug conjugate directed against Nectin-4, is associated with peripheral sensory neuropathy (SN) in the treatment of advanced urothelial cancers. A systematic literature review and meta-analysis were conducted to assess the overall incidence and risk of SN in patients receiving EV. Methods: A systematic search through mid-2022 of PubMed, Cochrane Library, and recent ASCO annual and genitourinary meetings was conducted to identify relevant studies. Eligible studies were clinical trials of patients with urothelial cancer receiving single-drug EV at the standard dose with data on SN available. Incidence and relative risk (RR) of SN were calculated using both a fixed-effects and a random-effects model. Results: Of the 93 initial publications identified, there were 5 trials that met the eligibility criteria and included a total 996 patients with 630 patients receiving EV at the standard dose. The summary incidence of all-grade SN was 42.3% (95% CI: 38.5-46.2%) with the incidence of high-grade SN being 3.1% (95% CI: 1.9-4.9%). In comparison with standard chemotherapy, there was no significant difference for EV in all-grade SN (RR = 0.95, 95% CI: 0.77-1.18, p = 0.66) and high-grade SN (RR = 1.69, 95% CI: 0.40-7.21, p = 0.48). In some cases, SN also led to discontinuation of EV (4.4%, 95% CI: 2.1-6.7%). Conclusions: EV is associated with a substantial toxicity of peripheral sensory neuropathy, and its risk may be comparable to that of standard chemotherapy. Further studies are needed to assess and reduce the risk of severe neuropathy.
Real world data for venous thromboembolisms (VTEs) in patients with active cancer: Thromboprophylaxis pooled analysis from GMaT and ACT4CAT studies.
Authors: Nikolaos Tsoukalas, Athina Christopoulou, Eleni Timotheadou, Anna Koumarianou, Alexandros Ardavanis, Ilias Athanasiadis, Stamatina G Demiri, Alexandros Bokas, Georgios Samelis, Stavros Peroukidis, George Papatsibas, Charalampos Andreadis, Achilleas Nikolakopoulos, Amanda Psyrri, Nikolaos Kapodistrias, Pavlos Papakostas, Gerasimos Aravantinos, Athanasios Athanasiadis, Pavlos Papakotoulas, Ioannis Boukovinas
Journal: Journal of Clinical Oncology (2023)

6637 Background: Venous Thromboembolisms (VTEs) lead to many negative consequences for patients with active cancer and are reported up to 20%. They affect anticancer treatment plan, increase morbidity, mortality, economic burden, and escalate psychological drain. Current guidelines recommend pharmacologic prophylaxis for thrombosis in ambulatory cancer patients with Khorana score ≥2. Methods: GMaT and ACT4CAT are prospective observational phase IV studies conducted by HeSMO in Greece. The aim was to record the clinical practice for ambulatory patients with active cancer who received thromboprophylaxis and enrolled after signing informed consent. Studies were approved by the bioethics committee. Results: 1157 patients from 26 oncology clinics enrolled who received thromboprophylaxis. Tumor types: gastrointestinal 38.5%, lung 24.8%, urological 12.2%, gynecological 6.9%, breast 6.1% and others 11.5%. Treatment lines: 1st 62.5%, 2nd 15.1%, 3rd 4%, adjuvant 9.7% and neoadjuvant 5.9%. Age ≥65 in 55.2%, BMI ≥30 in 17.8% and males 59.9%. High-Risk for Thrombosis Agents (HRTAs) received 82.3%: platinum agents (52.9%), antimetabolites (49.0%) and immunotherapy (10.2%). Notably, 52.7% of anticancer agents had potential drug-drug interactions (DDIs) with Direct Oral Anticoagulants (DOACs). High thrombotic risk factors presented in table. Thromboprophylaxis duration was 5.1±3.3 months with: tinzaparin 91.2%, fondaparinux 4.6%, bemiparin 2.3%, enoxaparin 1.2%, rivaroxaban 0.4% and apixaban 0.3%. Intermediate thromboprophylaxis doses of Low Molecular Weight Heparins (LMWHs) received 62% of patients; 50% in adjuvant setting &amp; 72.6% in metastatic. 32 thrombotic events reported (efficacy: 97.2%, 95%CI: 96.3-98.2%) and 26 grade 1 or minor bleedings (2.2%, 95%CI:1.4-3.1%). Patients receiving intermediate doses of LMWHs had less risk for thrombosis (p=0.0308). Conclusions: VTEs prophylaxis in ambulatory patients with active cancer was found safe and effective. Apart from Khorana score, metastasis, HRTAs and DDIs seem to affect clinical decision for thromboprophylaxis mainly with LMWHs and often using intermediate doses irrelevant of clinical setting. Cancer Associated Thrombosis (CAT) is not negligible risk for patients and oncologists appeared to be aware about this. Clinical trial information: NCT03292107 , NCT03909399 . [Table: see text]